The complement anaphylatoxins, C3a and C5a, are capable of inducing smooth muscle contraction and enhancing vascular permeability in addition to a number of other biological activities. Initial in vivo experiments showed that these peptides, instilled intrabronchially in guinea pigs, cause an acute inflammatory response. We have shown that the bronchospasms induced in vivo by C3a and C5a can be correlated with contractions of isolated peripheral airway preparations from guinea pig, and that the response can be quantitated as a function of concentration, thus facilitating pharmacologic examination of the response. It is already known that C3a and C5a are potent mediators of histamine release in lung and we have recently shown that C5a also stimulates release of metabolites of arachidonic acid, including the leukotrienes which make up slow-reacting substance of anyphylaxis (SRS-A). It is proposed that further investigations will now be conducted to elucidate the mechanism(s) by which the anaphylatoxins elicit their response in lung at a cellular and molecular level. The relative proportions of leukotrienes B4, C4 and D4 released by C5a will be determined since these three lipids have different specific sites of action on pulmonary tissue. The mediators released by C3a will be identified and quantitated using a similar approach. The cell type(s) responsible for anaphylatoxin-induced mediator release from lung will be identified by purification of individual cell types dispersed from the tissue and analysis of the products released. Similar experiments will be performed using human lung tissue stimulated by human C3a and C5a to compare the mediators released with those released from guinea pig lung and thus evaluate the potential importance of anaphylatoxin generation in human lung. Additional experiments will be directed toward evaluating the anaphylactoid activity of other potential mediators of inflammation using isolated tissue preparations. Finally, in vivo experiments will be conducted in guinea pigs to compare the pathophysiologic changes caused by secondary mediators released by anaphylatoxins with those caused by the anaphylatoxins themselves. These investigations will contribute significantly toward understanding the role of these potent humoral mediators in pulmonary disease processes.